Zinc-mediated chain extension reaction of 1,3-diketones to 1,4-diketones and diastereoselective synthesis of trans-1,2-disubstituted cyclopropanols

Article abstract of DOI:10.1021/jo051950b

A variety of 1,3-diketones can be efficiently converted into the corresponding 1,4-diketones and trans-1,2-disubstituted cyclopropanols by using organozinc species in one-pot reactions. It was found that 2.3 equiv of CF ₃CO₂ZnCH₂I was effective to give the corresponding chain-extended products in 44-85% yields, while a mixture of organozinc species formed from 4.0 equiv of Et₂Zn, 2.0 equiv of CF₃CO₂H, and 4.0 equiv of CH₂I₂ resulted in the formation of trans-1,2-disubstituted cyclopropanols with quite good yields and diastereoselectivity.

Full text of DOI:10.1021/jo051950b

Zinc-Mediated Chain Extension Reaction of 1,3-Diketones to
1,4-Diketones and Diastereoselective Synthesis of
trans-1,2-Disubstituted Cyclopropanols
Song Xue,* Le-Zhen Li, Yong-Kang Liu, and Qing-Xiang Guo
Department of Chemistry, UniVersity of Science and Technology of China,
Hefei 230026, People’s Republic of China
xuesong@ustc.edu.cn
ReceiVed September 16, 2005
A variety of 1,3-diketones can be efficiently converted into the corresponding 1,4-diketones and trans-
1,2-disubstituted cyclopropanols by using organozinc species in one-pot reactions. It was found that 2.3
equiv of CF3CO2ZnCH2I was effective to give the corresponding chain-extended products in 44-85%
yields, while a mixture of organozinc species formed from 4.0 equiv of Et2Zn, 2.0 equiv of CF3CO2H,
and 4.0 equiv of CH2I2 resulted in the formation of trans-1,2-disubstituted cyclopropanols with quite
good yields and diastereoselectivity.
Introduction
garding zinc-mediated conversion of 1,3-diketones to 1,4-
diketones under mild reaction conditions.
1,4-Diketones are important and valuable precursors for the
synthesis of substituted cyclopentenones,1,2 such as jasmones,
rethorolones, cuparenones, and prostaglandins, and of five-
membered heterocyclic compounds,3 such as furans, pyrroles,
thiophenes, and pyridazines. A variety of synthetic methods have
been developed for the preparation of 1,4-diketones.4-6 These
methods are efficient for the synthesis of 1,4-diketones, but most
of them follow lengthy procedures, require multistep preparation
of a special reagent, and utilize expensive transition-metal
complexes. Therefore, an simple and efficient methodology for
the synthesis of 1,4-diketones from facile materials is of great
interest. Here, we wish to report our preliminary results re-
In 1997, Zercher reported an operationally simple approach
to the chain extension of â-keto esters using the zinc reagent
EtZnCH2I.7 This reaction system could be extended to â-keto
amides8 and â-keto phosphonates.9 However, the reaction of
acyclic â-diketones, such as 2,4-pentanedione, with EtZnCH2I
resulted in no observable reaction.7a Very recently, free-radical-
(4) (a) Finch, N.; Fitt, J. J.; Hsu, I. H. C. J. Org. Chem. 1971, 36, 3191.
(b) Negishi, E.-I.; Luo, F.-T.; Pecora, A. J.; Silveira, A., Jr. J. Org. Chem.
1983, 48, 2427. (c) Rosini, G.; Ballini, R.; Sorrenti, P. Tetrahedron 1983,
39, 4127. (d) Pecunioso, A.; Menicagli, R. J. Org. Chem. 1988, 53, 2614.
(e) Arcadi, A.; Cacchi, S.; Marinelli, F.; Misiti, D. Tetrahedron Lett. 1988,
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Am. Chem. Soc. 1984, 106, 2149.
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S. P. Synth. Commun. 1984, 14, 469. (c) Takahashi, K.; Aihara, T.; Ogura,
K. Chem. Lett. 1987, 2359. (d) Pecuniso, A.; Menicagli, R. J. Org. Chem.
1988, 53, 2614. (e) Fiandanese, V.; Marchese, G.; Naso, F. Tetrahedron
Lett. 1988, 29, 3587. (f) Bergman, R.; Nilsson, B.; Wickberg, B. Tetrahedron
1990, 31, 2783.
(2) (a) Wenkert, E.; Buckwalter, B. L.; Craveiro, A. A.; Sanchez, E. L.;
Sathe, S. S. J. Am. Chem. Soc. 1978, 100, 1267. (b) Wenkert, E.; Greenberg,
R. S.; Ragu, M. S. J. Org. Chem. 1985, 50, 4681. (c) Curran, D. P.
Tetrahedron 1994, 58, 1181. (d) Roberts, S. M.; Santoro, M. G.; Sickle J.
J. Chem. Soc., Perkin Trans. 1 2002, 1735. (e) Banik, B. K.; Banik, I.;
Renteria, M.; Dasgupta, S. K. Tetrahedron Lett. 2005, 46, 2643.
(3) (a) Liu, Y. G.; Zhang, Y. M. Tetrahedron. 2003, 59, 8429. (b) Ho,
T. L. Polarity Control for Synthesis; Wiley: New York, 1991; Chapter 7.
(c) Amarnath, V.; Douglas, C. A.; Amarnath, K.; Valentine, W. M.;
Wetteran, L. A.; Graham, D. G. J. Org. Chem. 1991, 56, 6924.
(5) (a) Bergman, R.; Nilsson, R.; Wickberg, B. Tetrahedron Lett. 1990,
31, 2783. (b) Freeman, F.; Kim, D, S, H, J.; Rodriguez, E. J. Org. Chem.
1992, 57, 1722. (c) Wedler, C.; Schick, H. Synthesis 1992, 543. (c) Yuguchi,
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56, 5774. (b) Huang, J.-T.; Su, T.-L.; Watanabe, K. A. J. Org. Chem. 1991,
56, 4811. (c) Katritzky, A. R.; Zhang, G. F.; Jiang, J. L. J. Org. Chem.
1995, 60, 7605. (d) Matsumoto, S.; Okubo, Y.; Mikami, K. J. Am. Chem.
Soc. 1998, 120, 4015. (e) Yasuda, M.; Tsuji, S.; Shigeyoshi, Y.; Baba, A.
J. Am. Chem. Soc. 2002, 124, 7440. (f) Mattson, A. E.; Bharadwaj, A. R.;
Scheidt, K. A. J. Am. Chem. Soc. 2004, 126, 2314.
(7) (a) Brogan, J, B.; Zercher, C. K. J. Org. Chem. 1997, 62, 6444. (b)
Ronsheim, M. D.; Hilgenkamp, R.; Zercher, C. K. Org. Synth. 2002, 79,
146. (c) Lai, S.; Zercher, C. K.; Jasinski, J. P.; Reid, S. N.; Staples, R. J.
Org. Lett. 2001, 3, 4169. (d) Hilgenkamp, R.; Zercher, C. K. Org. Lett.
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68, 4535.
10.1021/jo051950b CCC: $33.50 © 2006 American Chemical Society
Published on Web 11/24/2005
J. Org. Chem. 2006, 71, 215-218
215

Xue et al.
TABLE 1. Chain Extension of 1,3-Diketones to 1,4-Diketones
promoted ring expansion and chain extension of 1,3-diketones
to give the corresponding 1,4-diketones was reported.10 To the
best of our knowledge, examples of preparing 1,4-diketones
from 1,3-diketones have not been described using zinc reagents.
Our interest in CF3COOH enhancing the reactivity of zinc
reagents prompted us to verify the possibility of the zinc-
mediated synthesis of 1,4-diketones from 1,3-diketones.11
Results and Discussion
As the zinc species CF3CO2ZnCH2I shows high activity in
the cyclopropanation of olefins,12 our initial efforts were directed
at the application of CF3CO2ZnCH2I to commercially available
2,4-pentanedione. According to this procedure,12b 1 equiv of
diethylzinc was combined with 1 equiv of trifloroacetic acid to
form CF3CO2ZnEt, which was then reacted with 1 equiv of
methylene iodide to generate the cyclopropanation reagent
CF3CO2ZnCH2I. It is fortunate to find that the chain-extended
product 2,5-hexanedione was detected by GC-MS analysis when
2,4-pentanedione was added to the in situ generated zinc species.
To obtain the isolated yield, a high-boiling-point substrate was
used in this reaction. Treatment of 6-phenyl-2,4-hexanedione
with 2.3 equiv of CF3CO2ZnCH2I at room temperature for 5 h
provided the chain-extended product 2a in 44% yield. Although
unreacted starting material was observed at this stoichiometry
of zinc reagent, prolonging the reaction time resulted in no
obvious effect on the reaction yield. A variety of 1,3-diketones
were then allowed to react with the zinc species; these results
are summarized in Table 1. Both aromatic and aliphatic 1,3-dike-
tones can be employed as starting materials. Aromatic 1,3-dike-
tones provided the corresponding chain-extended products in
good isolated yields. Substitution of an electron-donating group
on the aromatic ring gave a higher yield than that of an electron-
withdrawing group on the aromatic ring. More hindered 1,3-
diketones were less efficient and gave moderate yields. Although
CF3CO2ZnCH2I was found to accelerate the cyclopropanation
reaction of olefins dramatically compared to the Furukawa
reagent EtZnCH2I, the 1,3-diketone which contained an electron-
deficient alkene underwent selective chain extension in prefer-
ence to cyclopropanation of the olefin under the standard reac-
tion conditions. This zinc-mediated process to synthesize sym-
metrical and unsymmetrical 1,4-diketones holds many distinct
advantages over the previously reported methods. The most
obvious advantages are no lengthy procedures and no require-
ment of multistep preparation of a special reagent, especially
avoiding utilizing expensive transition-metal complexes.
The chain extension reaction worked very well for simple
acyclic and aromatic 1,3-diketones, especially for aromatic 1,3-
diketones. However, no reaction was observed when R-substi-
tuted â-diketone was submitted to this reaction. For example,
2-methyl-1-phenylbutane-1,3-dione gave no reaction under the
typical reaction conditions (entry 17, Table 1).
a Isolated yields. b Performed at 0 °C for 5 h. c Performed with 2.0 equiv
of CF3CO2ZnCH2I. d NR ) no reaction.
SCHEME 1. Plausible Mechanism of the Chain Extension
Reaction
reaction is formation of the enolate 3, which consumes 1 equiv
of CF3CO2ZnCH2I. Enolate 3 then undergoes cyclopropanation
with a second equivalent of the zinc species to give the
cyclopropyl intermediate 4, followed by cleavage to give the
intermediate 5 or 6, and the reaction is then quenched by
saturated aqueous NH4Cl to provide the chain-extended product
2. The chain extension reaction proceeded smoothly under these
reaction conditions. The reason may be that ionization of the
electron-deficient CF3CO2 group creates a vacant coordination
site on the zinc, permitting coordination of the iodine that results
in activation of the methylene group toward reaction with
enolate, resulting in the efficient formation of intermediate 4.12b
In the process of the chain extension reaction of 1,3-diketone
to 1,4-diketone, when the amount of CF3CO2ZnCH2I was
increased to over 2.3 equiv, the desired product yield decreased,
and a new polar compound was found. For example, exposure
of 1-phenylbutane-1,3-dione to 3.3 equiv of CF3CO2ZnCH2I
gave the desired product 2c in 55% yield, along with a 31%
yield of a new polar compound. This compound was determined
to be 7a by NMR and HRMS spectra. The relative stereochem-
On the basis of the work of Zercher,7 a plausible mechanism
for the reaction is shown in Scheme 1. The first step of the
(8) Hilgenkamp, R.; Zercher, C. K. Tetrahedron 2001, 57, 8793.
(9) Verbicky, C. A.; Zercher, C. K. J. Org. Chem. 2000, 65, 5615.
(10) Mu, X. J.; Zou, J. P.; Wang, Z. T.; Zhang, W. Tetrahedron Lett.
2005, 46, 4727.
(11) (a) Xue, S.; Li, Y. L.; Han, K. Z.; Yin, W.; Wang, M.; Guo, Q. X.
Org. Lett. 2002, 4, 905. (b) Xue, S.; He, L.; Han, K. Z.; Liu, Y. K.; Guo,
Q. X. Synlett 2005, 8, 1247. (c) Xue, S.; Liu, Y. K.; Li, L. Z.; Guo, Q. X.
J. Org. Chem. 2005, 70, 8245.
(12) (a) Yang, Z.; Lorenz, J. C.; Shi, Y. Tetrahedron Lett. 1998, 39,
8621. (b) Lorenz, J. C.; Long, J.; Yang, Z. Q.; Xue, S.; Xie, Y. N.; Shi, Y.
J. Org. Chem. 2004, 69, 327.
216 J. Org. Chem., Vol. 71, No. 1, 2006

Zinc-Mediated Chain Extension Reaction
and regioselectivity as well. When the R2 group varied from a
methyl to an ethyl group, the yield of isomer 8d increased to
25%, but that of cyclopropanol 7d decreased obviously (entries
3 and 4, Table 2). A propyl group resulted in a dramatic loss of
yield (entries 1 and 5, Table 2). These results suggest that the
yield of isomer 8 increased, but the combined yields of 7 and
8 decreased, when R2 was a bulky group. It is notable that
even when R2 was a propyl group, a substrate with an elec-
tron-donating group on the aromatic ring could afford the sole
product 7f in 94% yield. For aliphatic 1,3-diketones, the cor-
responding cyclopropanols were obtained in moderate yields.
TABLE 2. Diastereoselective Synthesis of Trans-1,2-Disubstituted
Cyclopropanols
product 7
product 8
entry
R1
R2
(yield,a %)
(yield,a %)
1
2
3
4
5
6
7
8
C6H5
Me
Me
Me
CH3CH2
CH3CH2CH2
CH3CH2CH2
C6H5
C6H5
C6H5
Me
Me
7a (93)
7b (95)
7c (70)
7d (41)
7e (45)
7f (94)
7g (61)
7h (73)
7i (18)
7j (60)
7k (43)
7l (61)
7m (65)
8a (0)
8b (0)
8c (14)
8d (25)
8e (12)
8f (0)
p-MeOC6H5
p-ClC6H5
p-ClC6H5
C6H5
p-MeOC6H5
C6H5
p-MeOC6H5
p-ClC6H5
2-thienyl
C6H5CH2CH2
CH3CH2
Me
Conclusions
In summary, we have identified a simple and efficient syn-
thetic methodology for the synthesis of 1,4-diketones and 1,2-
disubstituted cyclopropanols from 1,3-diketones by using or-
ganozinc reagents in a one-pot reaction. The chain-extended
1,4-diketone products were obtained in moderate to good yields.
Excess amounts of zinc species gave cyclopropanols with good
yields and diastereoselectivity. Although the reaction worked
well for R-unsubstituted â-diketones, no reaction was observed
for acyclic R-substituted â-diketones. Efforts are underway to
define more clearly the scope and synthetic utility of this chain
extension reaction.
8h (<3)
8i (47)
8j (0)
9
10
11
12
13
8k (20)
CH3CH2
Me
a Isolated yields.
istry of methyl and alkyl substituents of the cyclopropanol 7a
was absolutely trans, which was firmly established by NOESY
studies.13 The completely diastereoselective synthesis of the 1,2-
disubstituted cyclopropanol 7a may be due to the zinc enolate
intermediate 6 proceeding through carbonyl oxygen complex-
ation to zinc to form a seven-membered-ring transition state,
and then enolate 6 undergoes cyclopropanation with a third
equivalent of the zinc species to give the cyclopropyl alcohol
intermediate. Cyclopropanols are valuable in synthetic practice
as useful intermediates14 and as important substances capable
of possessing different kinds of biological activity.15 Therefore,
we attempted to develop a new methodology to synthesize trans-
1,2-disubstituted cyclopropanols from 1,3-diketones.
Through an effort to optimize the reaction conditions, it is
found that a mixture of zinc species formed from 4.0 equiv of
Et2Zn, 2.0 equiv of CF3CO2H, and 4.0 equiv of CH2I2 resulted
in its clean and efficient conversion to compound 7a in 93%
yield at room temperature for 4 h.16 The substituents on the
benzene ring have a remarkable effect on the reaction. These
can be seen from Table 2; the substrate with an electron-donating
group on the aromatic ring gave the desired product 7b in excel-
lent yield. When the substrate contained an electron-withdrawing
group on its aromatic ring, its regioselective isomer 8 was
obtained, but still maintaining absolute diastereoselectivity. For
example, 1-(4-chlorophenyl)butane-1,3-dione, which has an
electron-withdrawing group on the aromatic ring, provided the
product 7c in 70% yield along with isomer 8c in 14% yield.
The two isomers 7c and 8c were easily assigned on the basis of
1H NMR spectra, since proton signals of the methyl group (R2)
were singlets at δ 1.50 and 2.23, respectively. At the same time,
the steric hindrance effect has an obvious influence on the yield
Experimental Section
General Procedure for the Preparation of 1,4-Diketones from
1,3-Diketones using Organozinc Reagents. A 50 mL round-
bottom flask was equipped with a stir bar and charged with freshly
distilled methylene chloride (4 mL), and diethylzinc (70 µL, 0.69
mmol) was added via syringe under nitrogen. The solution was
cooled in an ice bath, and trifluoroacetic acid (54 µL, 0.69 mmol)
was then dropped very slowly into the reaction mixture via syringe.
After the mixture was stirred for 30 min, CH2I2 (58 µL, 0.69 mmol)
was added dropwise via syringe under nitrogen. After an additional
30 min of stirring at 0 °C, the 1,3-diketone (0.3 mmol) was added
as quickly as possible, and the ice bath was removed. The reaction
mixture was stirred for 5 h at room temperature. The solution was
quenched by saturated aqueous ammonium chloride solution and
extracted with diethyl ether (3 × 10 mL). The combined organic
layers were washed with brine and then dried over anhydrous
magnesium sulfate, filtered, and concentrated on the rotary evapora-
tor. The desired product was isolated by silica gel chromatography
with petroleum ether/EtOAc (20:1-5:1).
1-Phenylheptane-1,4-dione (2d). Light yellow oil (51% yield).
1H NMR (300 MHz, CDCl3; δ, ppm): 7.91 (d, J ) 7.2 Hz, 2H),
7.49 (t, J ) 7.2 Hz, 1H), 7.38 (t, J ) 7.2 Hz, 2H), 3.21(t, J ) 6.6
Hz, 2H), 2.78 (t, J ) 6.6 Hz, 2H), 2.44 (t, J ) 7.2 Hz, 2H), 1.59
(m, 2H), 0.87 (t, J ) 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3; δ,
ppm): 209.8, 198.8, 136.8, 133.2, 128.7, 128.1, 45.0, 36.3, 32.4,
17.4, 13.9. IR (neat; cm-1): V 3062, 2962, 2933, 2875, 1714, 1686,
1359, 746, 690. HRMS (EI): calcd for C13H16O2 (M+), 204.1150;
found, 204.1159.
1-(4-Methoxyphenyl)heptane-1,4-dione (2g). The title com-
pound was prepared according to the general procedure, except that
the reaction mixture was stirred for 5 h at 0 °C and then purified
by chromatography on silica gel (10:1 petroleum ether/EtOAc) to
(13) See the Supporting Information for details.
(14) (a) De Puy, C. H. Acc. Chem. Res. 1968, 1, 33. (b) Salaun, J. Top.
Curr. Chem. 1988, 144, 1. (c) Salaun, J. Chem. ReV. 1989, 89, 1247. (d)
Kulinkovich, O. G. Chem. Res. 2003, 103, 2597.
(15) (a) Liu, H. U.; Walsh, C. T. In The Chemistry of the Cyclopropyl
Group; Rappoport, Z., Ed.; Wiley: London, 1987; p 959. (b) Suckling, C.
J. Angew. Chem., Int. Ed. Engl. 1988, 27, 537. (c) Salaun, J.; Baird, M. S.
Curr. Med. Chem. 1995, 2, 511. (d) Salaun, J. Top. Curr. Chem. 2000,
207, 1.
1
give a light yellow solid (50% yield). Mp: 39-40 °C. H NMR
(300 MHz, CDCl3; δ, ppm): 7.90 (d, J ) 8.9 Hz, 2H), 6.85 (d, J
) 8.9 Hz, 2H), 3.80 (s, 3H), 3.17 (t, J ) 6.3 Hz, 2H), 2.76 (t, J )
6.3 Hz, 2H), 2.44 (t, J ) 7.5 Hz, 2H), 1.58 (dt, J ) 7.5 Hz, 2H),
0.86 (t, J ) 7.5 Hz, 3H). 13C NMR (75 MHz, CDCl3; δ, ppm):
210.0, 197.3, 163.6, 130.4, 129.9, 113.8, 55.6, 45.0, 36.4, 32.1,
17.4, 13.9. IR (neat; cm-1): V 2961, 1713, 1677, 1600, 1259, 1169,
1025, 834. HRMS (EI): calcd for C14H18O3 (M+), 234.1256; found,
234.1252.
(16) Treatment of 4.0 equiv of CF3CO2ZnCH2I with 1-phenylbutane-
1,3-dione gave 7a in 63% yield along with a 31% yield of the chain-extended
product 2c.
J. Org. Chem, Vol. 71, No. 1, 2006 217

Xue et al.
1-(4-Chlorophenyl)hexane-1,4-dione (2i). White solid (54%
yield). Mp: 86-87 °C. 1H NMR (300 MHz, CDCl3; δ, ppm): 7.86
(d, J ) 8.6 Hz, 2H), 7.36 (d, J ) 8.6 Hz, 2H), 3.18 (t, J ) 6.6 Hz,
2H), 2.79 (t, J ) 6.6 Hz, 2H), 2.48 (q, J ) 7.2 Hz, 2H), 1.02 (t, J
) 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3; δ, ppm): 210.1, 197.6,
139.7, 135.1, 129.6, 129.0, 36.2, 35.9, 32.5, 7.9. IR (neat; cm-1):
V 2981, 2939, 1708, 1671, 1588, 1089, 848, 799. HRMS (EI): calcd
for C12H13O2Cl (M+), 224.0604; found, 224.0605.
δ, ppm): 200.3, 163.7, 130.7, 129.9, 113.9, 55.6, 54.6, 37.5, 25.8,
20.9, 19.9. IR (neat; cm-1): V 3441, 1667, 1260, 1025. HRMS
(EI): calcd for C13H16O3 (M+), 220.1099; found, 220.1105.
1-(4-Chlorophenyl)-2-(2-hydroxy-2-methylcyclopropyl)etha-
none (7c). Light yellow oil (70% yield). 1H NMR (300 MHz,
CDCl3; δ, ppm): 7.92 (d, J ) 6.6 Hz, 2H), 7.45 (d, J ) 6.6 Hz,
2H), 3.46 (dd, J ) 17.4, 5.1 Hz, 1H), 2.85 (dd, J ) 17.4, 9.0 Hz,
1H), 2.23 (br s, 1H), 1.50 (s, 3H), 0.99 (m, 1H), 0.75 (dd, J ) 9.0,
5.7 Hz, 1H), 0.55 (t, J ) 5.7 Hz, 1H). 13C NMR (75 MHz, CDCl3;
δ, ppm): 200.2, 139.8, 135.3, 129.7, 129.1, 54.7, 38.0, 25.8. 20.5,
19.9. IR (neat; cm-1): V 3425, 1714, 1221, 1092. HRMS (EI): calcd
for C12H13O2Cl (M+), 224.0604; found, 224.0608.
1-[2-(4-Chlorophenyl)-2-hydroxycyclopropyl]propan-2-one (8c).
Light yellow oil (14% yield). 1H NMR (300 MHz, CDCl3; δ,
ppm): 7.32-7.26 (m, 4H), 3.03 (dd, J ) 17.2, 5.1 Hz, 1H), 3.00
(br s, 1H), 2.51 (dd, J ) 17.2, 8.7 Hz, 1H), 2.22 (s, 3H), 1.31 (m,
2H), 0.95 (dd, J ) 5.7, 5.7 Hz, 1H). 13C NMR (75 MHz, CDCl3;
δ, ppm): 210.0, 143.0, 132.5, 128.5, 126.5, 58.2, 42.8, 30.3, 23.3,
22.3. IR (neat; cm-1): V 3411, 1707, 1092, 1012. HRMS (EI): calcd
for C12H13O2Cl (M+), 224.0604; found, 224.0609.
(E)-1,6-Diphenylhex-5-ene-1,4-dione (2k). White solid (85%
1
yield). Mp: 109-111 °C. H NMR (300 MHz, CDCl3; δ, ppm):
7.95 (d, J ) 6.9, 2H), 7.49 (d, J ) 16.2 Hz, 1H), 7.51-7.32 (m,
9H), 6.79 (d, J ) 16.2 Hz, 1H), 3.34 (t, J ) 6.6 Hz, 2H), 3.10 (t,
J ) 6.6 Hz, 2H). 13C NMR (75 MHz, CDCl3; δ, ppm): 198.8,
143.0, 136.8, 134.6, 133.3, 129.1, 128.7, 128.5, 128.3, 126.26, 33.6,
32.7. IR (neat; cm-1): V 2903, 1686, 1615, 1098, 750, 689. HRMS
(EI): calcd for C18H16O2 (M+), 264.1150; found, 264.1143.
1-Naphthalen-2-ylpentane-1,4-dione (2o). Light yellow solid
(65% yield). Mp: 82-84 °C. 1H NMR (300 MHz, CDCl3; δ,
ppm): 8.45 (s, 1H), 7.95 (d, J ) 8.2 Hz, 1H), 7.95 (d, J ) 8.2 Hz,
1H), 7.81 (m, 2H), 7.48 (m, 2H), 3.36 (t, J ) 6.0 Hz, 2H), 2.88 (t,
J ) 6.0 Hz, 2H), 2.22 (s, 3H). 13C NMR (75 MHz, CDCl3; δ,
ppm): 207.6, 198.6, 135.8, 134.1, 132.7, 129.9, 129.7, 128.6, 128.6,
127.9, 126.9, 123.9, 37.3, 32.6, 30.3. IR (neat; cm-1): V 3058, 1713,
1677, 1408, 1306, 1125, 819, 757. HRMS (EI) calcd for C15H14O2
(M+), 226.0994; found, 226.0995.
1-(4-Chlorophenyl)-2-(2-ethyl-2-hydroxycyclopropyl)etha-
1
none (7d). Light yellow oil (41% yield). H NMR (300 MHz,
CDCl3; δ, ppm): 7.93 (d, J ) 9.0 Hz, 2H), 7.45 (d, J ) 9.0 Hz,
2H), 3.48 (dd, J ) 17.1, 5.1 Hz, 1H), 2.85 (dd, J ) 17.1, 8.8 Hz,
1H), 2.35 (br s, 1H), 1.67-1.56 (m, 2H), 1.05 (m, 3H), 0.76 (dd,
J ) 9.1, 5.6 Hz, 1H), 0.52 (t, J ) 5.6 Hz, 1H). 13C NMR (75
MHz, CDCl3; δ, ppm): 200.3, 139.8, 135.3, 129.8, 129.1, 59.1,
37.9, 32.2, 19.7, 18.9, 9.7. IR (neat; cm-1): V 3429, 1714, 1173,
1092. HRMS (EI): calcd for C13H15O2Cl (M+), 238.0761; found,
238.0757.
1-[2-(4-Chlorophenyl)-2-hydroxycyclopropyl]butan-2-one (8d).
Light yellow oil (25% yield). 1H NMR (400 MHz, CDCl3; δ,
ppm): 7.32-7.25 (m, 4H), 3.18 (br,s, 1H), 3.11 (dd, J ) 16.8, 4.8
Hz, 1H), 2.48 (m, 3H), 1.27 (m, 2H), 1.07 (t, J ) 7.6 Hz, 3H),
0.98 (t, J ) 6.4 Hz, 1H). 13C NMR (100 MHz, CDCl3; δ, ppm):
212.9, 143.2, 132.3, 129.0, 128.4, 58.1, 41.6, 36.4, 23.6, 22.5, 7.6.
IR (neat; cm-1): V 3440, 2972, 2938, 1709, 1684, 1589, 1092.
HRMS (EI): calcd for C13H15O2Cl (M+), 238.0761; found,
238.0762.
1-(4-Chlorophenyl)-2-(2-hydroxy-2-phenylcyclopropyl)etha-
none (7i). Light yellow oil (18% yield). 1H NMR (300 MHz,
CDCl3; δ, ppm): 7.96 (dd, J ) 8.7, 1.8 Hz, 2H), 7.46-7.23 (m,
7H), 3.66 (dd, J ) 17.4, 5.1 Hz, 1H), 3.04 (dd, J ) 17.4, 9.0 Hz,
1H), 2.93 (br s, 1H), 1.35 (dd, J ) 9.6, 5.7 Hz, 1H), 1.04 (t, J )
6.3 Hz, 1H). 13C NMR (75 MHz, CDCl3; δ, ppm): 199.8, 144.2,
139.9, 135.1, 129.7, 129.0, 128.4, 126.8 125.2, 58.9, 37.7, 23.2,
22.1. IR (neat; cm-1): V 3426, 1681. HRMS (EI): calcd for
C17H15O2Cl (M+), 286.0761; found, 286.0759.
2-[2-(4-Chlorophenyl)-2-hydroxycyclopropyl]-1-phenyletha-
none (8i). Light yellow solid (47% yield). Mp: 71-73 °C. 1H NMR
(300 MHz, CDCl3; δ, ppm): 7.92 (d, J ) 8.4 Hz, 2H), 7.54 (t, J
) 8.4 Hz, 1H), 7.41 (t, J ) 8.4 Hz, 2H), 7.30-7.18 (m, 4H), 3.70
(dd, J ) 17.1, 4.8 Hz, 1H), 3.12 (br s, 1H), 2.90 (dd, J ) 17.1, 9.3
Hz, 1H), 1.46-1.40 (m, 1H), 1.24 (dd, J ) 9.3, 5.7 Hz, 1H), 1.00
(t, J ) 6.3 Hz, 1H). 13C NMR (75 MHz, CDCl3; δ, ppm): 201.3,
143.2, 136.7, 133.6, 132.4, 128.8, 128.5, 128.4, 126.7, 58.4, 37.8,
23.6, 22.5. IR (neat; cm-1): V 3449, 1680, 1343, 1279, 1092, 1008.
HRMS (EI): calcd for C17H15O2Cl (M+), 286.0761; found,
286.0764.
1
1-Thiophen-2-ylpentane-1,4-dione (2p). Oil (62% yield). H
NMR (300 MHz, CDCl3; δ, ppm): 7.76 (dd, J ) 3.8, 0.9 Hz, 1H),
7.63 (dd, J ) 4.9, 0.9 Hz, 1H), 7.13 (dd, J ) 4.9, 3.8 Hz, 1H),
3.22 (t, J ) 6.5 Hz, 2H), 2.88 (t, J ) 6.5 Hz, 2H), 2.24 (s, 3H).
13C NMR (75 MHz, CDCl3; δ, ppm): 207.1, 191.6, 143.8, 133.6,
132.1, 128.2, 37.1, 33.1, 30.1. IR (neat; cm-1): V 2921, 2253, 1717,
1665, 1416. HRMS (EI): calcd for C9H10O2S (M+), 182.0402;
found, 182.0394.
General Procedure for the Synthesis of Trans-1,2-Disubsti-
tuted Cyclopropanols from 1,3-Diketones Using Organozinc
Reagents. A 50 mL round-bottom flask was equipped with a stir
bar and charged with freshly distilled methylene chloride (4 mL),
and diethylzinc (120 µL, 1.20 mmol) was added via syringe under
nitrogen. The solution was cooled in an ice bath, and trifluoroacetic
acid (47 µL, 0.6 mmol) was then dropped very slowly into the
reaction mixture via syringe. After it was stirred for 30 min,
diiodomethane (98 µL, 1.20 mmol) was added dropwise via syringe
under nitrogen. After an additional 30 min of stirring at 0 °C, the
1,3-diketone (0.3 mmol) was added as quickly as possible, and the
ice bath was removed. The reaction mixture was stirred for 4 h at
room temperature until TLC indicated complete consumption of
the starting 1,3-diketone. The solution was quenched by saturated
aqueous ammonium chloride solution at 0 °C and extracted with
diethyl ether (3 × 10 mL). The combined organic layers were
washed with brine and then dried over anhydrous magnesium
sulfate, filtered, and concentrated on the rotary evaporator. The
desired product was isolated by silica gel chromatography with
petroleum ether/EtOAc (15:1-5:1).
2-(2-Hydroxy-2-methylcyclopropyl)-1-phenylethanone (7a).
Light yellow oil (93% yield). 1H NMR (300 MHz, CDCl3; δ,
ppm): 7.98 (d, J ) 7.4 Hz, 2H), 7.57 (t, J ) 7.4 Hz, 1H), 7.47 (t,
J ) 7.4 Hz, 2H), 3.55 (dd, J ) 17.2, 5.1 Hz, 1H), 3.85 (dd, J )
17.2, 9.0 Hz, 1H), 2.45 (br s, 1H), 1.50 (s, 3H), 1.25-0.97 (m,
1H), 0.76 (dd, J ) 9.1, 5.8 Hz, 1H), 0.56 (dd, J ) 5.8 Hz). 13C
NMR (75 MHz, CDCl3; δ, ppm): 201.6, 137.0, 133.3, 128.8, 128.3,
54.7, 38.0, 25.9, 20.7, 19.9. IR (neat; cm-1): V 3428, 1681, 1264,
1215, 753. HRMS (EI): calcd for C12H14O2 (M+), 190.0994; found,
190.0988.
Acknowledgment. We express our appreciation to the
National Natural Science Foundation of China (20202009) for
financial support.
2-(2-Hydroxy-2-methylcyclopropyl)-1-(4-methoxyphenyl)-
ethanone (7b). Light yellow oil (95% yield). 1H NMR (300 MHz,
CDCl3; δ, ppm): 7.91 (d, J ) 9.6 Hz, 2H), 6.88 (d, J ) 9.6 Hz,
2H), 3.80 (s, 3H), 3.49 (dd, J ) 16.8, 4.9 Hz, 1H), 2.66 (dd, J )
16.8, 9.1 Hz, 1H), 1.41 (s, 3H), 0.88 (m, 1H), 0.68 (dd, J ) 9.0,
5.7 Hz, 1H), 0.49 (t, J ) 5.7 Hz, 1H). 13C NMR (75 MHz, CDCl3;
Supporting Information Available: 1H and 13C NMR spectra
for products 2a-c,e,f,h,j,l-n, 7a,e, 8e, 7f-h,j,k, 8k, and 7l,m.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO051950B
218 J. Org. Chem., Vol. 71, No. 1, 2006